a. Field of Invention
This invention relates to a process for the optical resolution of the racemic organic bases, (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-isopropyl-2,3,4,4a,8,9,13b,1 4-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]-pyrido[2,1-a]isoquinolin-3-ol and (.+-.)-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-tert-butyl-2,3,4,4a,8,9,13b, 14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol into their corresponding (+)-enantiomers.
B. Prior Art
For convenience, (4a,13b-trans)-(3-hydroxy,13b-trans)-3-isopropyl-2,3,4,4a,8,9,13b,14-octah ydro-1H-benzo[6,7]cyclohepta[1,2,3-de]-pyrido[2,1-a]isoquinolin-3-ol is hereafter designated as Compound I and (4a,13b-trans)-(3-hydroxy,13b-trans)-3-tert-butyl-2,3,4,4a,8,9,13b,14-octa hydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol is hereafter designated as Compound II.
Compounds I and II are neuroleptic agents with essentially all the activity residing in the (+)-optically active enantiomer. The racemic form of Compound II is known generically as "butaclamol", see L. G. Humber and F. Bruderlein, Abstracts of Papers of the 167th Am. Chem. Soc. Meeting, Los Angeles, California, Division of Medicinal Chemistry, Paper No. 5; Apr. 1-5, 1974; and K. Voith, ibid (Paper No. 6). The (+)-form of Compound I is known generically as "dexclamol". The preparation of the racemic mixture of Compounds I and II is described in U.S. Pat. No. 3,914,305, issued Oct. 21, 1975 and U.S. Pat. No. 3,852,452 issued Dec. 3, 1974; see also Belgian Pat. No. 762,595, issued Aug. 5, 1971. In these Patents Compounds I and II are recited as 5-isopropyl-and 5-tert-butyl-1,4,5,6,6a,10,11,15-b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3 -de]pyrido[2,1-a]isoquinolin-5-ol (Isomer A), respectively. Compounds I and II are described in U.S. patent application U.S. No. 518,853, filed Oct. 29, 1974, now U.S. Pat. No. 3,985,751.
Prior to the present disclosure the resolution of racemic organic bases was usually performed by procedures requiring several steps of multiple recrystallizations. Because of time and expense required for such procedures, the need for an efficient resolution of the above noted racemic organic bases, Compounds I and II, is highly desirable.
Accordingly, a process is described here which avoids multiple recrystallizations and resolves the above noted bases in a commercially feasible operation and in high yield.